Over the past several years, the TH1/TH2 paradigm forming the basis of T cell immunology has expanded rapidly from the discovery of TH17 cells, a subset of CD4+ T memory cells characterized by their unique ability to secrete IL-17 family cytokines. Most importantly, TH17 cells appear to be intimately involved in innate immunity and autoimmunity. Sjvgren's syndrome (SjS) is an autoimmune disease affecting primarily of the salivary and lacrimal glands characterized by exocrine gland dysfunction. In recent years, NOD and NOD-derived mice have been shown to exhibit a disease that closely parallels SjS, including the loss of fluid secretions concomitant with the appearance of leukocyte infiltrates within the salivary and lacrimal glands. This autoimmune exocrinopathy has been separated into two major phases: first, numerous pathophysiologic changes occur within the exocrine glands independent of any autoimmune attack, and second, a progressive chronic autoimmune response resulting in loss of acinar cell mass and decline in exocrine function. Immunohistochemical staining of submandibular glands from C57BL/6.NOD-Aec1Aec2 mice (as well as salivary gland biopsies from SjS patients) has now shown strong positive staining for both IL-17 and IL-23 within the lymphocytic foci, plus a diffuse, sparsely staining of epithelial tissues. Temporal expressions of IL-17 and IL-23 in submandibular glands of C57BL/6.NOD-Aec1Aec2 mice correlated with expression of ROR3t, the TH17 cell master control gene. At the same time, more recent work has shown that IL-27, the cytokine that down-regulates TH17 activity, is expressed at very low levels in the exocrine glands. These results suggest that the TH17/IL-17/ IL-23 system is not only up-regulated in the exocrine glands of C57BL/6.NOD-Aec1Aec2 mice (and SjS patients) at time of disease, but may contribute to the clinical manifestations of the disease. In this grant application, we propose to study the importance of this TH17/IL-17/ IL-23 - IL-27 interactive system in the development and onset of SjS. To achieve this goal two aims are advanced: (i) define and characterize the IL-23 secreting and CD4+ TH17 memory T cell populations infiltrating the salivary glands during development of SjS- like disease, and (ii) determine a possible regulatory potential of IL-27 on the CD4+ TH17 memory T cell populations for preventing development of SjS using a gene therapy approach in the C57BL/6.NOD-Aec1Aec2 mouse model of SjS. Results from this study are expected to provide insight into the inter-relationship(s) between the LF-associated TH17 / IL-23 system and its regulatory IL-27 system in the development and sustainability of the autoimmune response leading to salivary gland dysfunction. Identification of molecular and cellular mechanisms involved in the development and onset of SjS, focusing specifically on biological changes associated with secretory dysfunction at a molecular level, should point to a variety of new and novel pathways permitting development of immunotherapy. A gene therapy approach directed towards regulating the TH17/IL-17/ IL-23 system through IL-27 would be a highly feasible method if results of the current study provide evidence that TH17 cells play an active role in the development and/or onset of SjS PUBLIC HEALTH RELEVANCE: TH1/TH2 paradigm, forming the basis of T cell immunology for decades, has been challenged by the discovery of TH17 cells, a subset of CD4+ T memory cells characterized by their unique ability to secrete IL-17 family cytokines and apparently involved in autoimmunity. In this grant application, we propose to utilize a gene therapy approach to study the possible role of the TH17/IL-17/ IL-23 - IL-27 interactive system in the development and onset of Sjvgren's syndrome (SjS), an autoimmune disease leading to dry mouth and dry eye syndromes. Identification of molecular and cellular mechanisms involved in the development and onset of SjS, focusing specifically on biological changes regulated by TH17/IL-17/ IL-23 / IL-27 and associated with secretory dysfunction, should point to a variety of new and radical targets permitting development of immunotherapy to treat SjS.